Maintaining data integrity in randomized clinical trials

BACKGROUND: The process of attaining and maintaining data integrity is critical to ensure a successful randomized clinical trial. Methodologic strategies to achieve data integrity when repeated measures are used has not been discussed in detail in the literature. The National Institutes of Health requires that data integrity and safety monitoring boards or plans be established for randomized clinical trials. OBJECTIVES: The objectives of this paper are to (a) examine important data collection issues nurse scientists often encounter in randomized clinical trials and (b) present a process that researchers can apply to achieve data integrity. METHODS: The process to achieve data integrity is based on strategies that were developed by an interdisciplinary hospice research team involved in an ongoing National Institutes of Health-funded clinical trial. The process and key issues are illustrated with methodologic examples from the randomized clinical trial and supporting literature. RESULTS: The process of achieving data integrity involves developing protocols in three key areas: data collection, training of data collectors, and data monitoring. The use of these protocols will increase the rigor of the clinical trial and assist in maintaining study validity. CONCLUSIONS: Investigators conducting clinical trials need to consider all issues involved in achieving data integrity and have tested protocols in place throughout the study. These approaches will not only help maintain study validity but also help ensure data of sufficient quantity and quality to achieve the desired statistical power.     

Threats to validity in randomized clinical trials

The purposes of this article are to present an overview of randomized clinical trials (RCTs) and describe some of the methodological problems inherent in using RCTs in nursing research. Many nursing intervention studies are fraught with problems that defy the stringent control criteria required for RCTs, leading to biased estimates of intervention efficacy. Five threats to validity in RCTs are presented, including problems related to (a) differential dropout, (b) random assignment, (c) identifying and maintaining an adequate control condition, (d) nonadherence to research protocols, and (e) assessment of clinically meaningful change. Three strategies are recommended for addressing some of the problems posed by RCTs and improving inference.     

Patient expectations in placebo-controlled randomized clinical trials

OBJECTIVE: To explore participants' experience in placebo-controlled randomized clinical trials (RCTs) specifically in relationship to their expectations. BACKGROUND: Aspects of being in RCTs, such as informed consent, perception of benefit and understanding of randomization, have been examined. In contrast, little is known concerning the formation of patient expectations before and during trials. METHODS: Qualitative methods using in-depth interviews with a semi-structured interview guide of nine patients from four different RCTs. Data analysis was conducted using a codebook format arranging participant responses under broad analytical headings. The interviewer used a semi-structured interview guide to direct the conversation from one broad topic to the next within the context of the ongoing conversation. A checklist of topics encouraged participants to describe their experiences in RCTs. Narratives concerning expectation, blinding and placebo were compared to identify common themes. RESULTS: Patient anticipatory processes were influenced and modified both before and during the trial from multiple inputs. Such factors as past experiences in RCTs, past experiences of ineffective treatment, stress of being off regular medications, fear of being a 'placebo responder', input of non-study doctors or other health professionals, the experience of other participants, measurements of health parameters made during the trial and the presence or absence of side-effects all affected patient expectation. CONCLUSION: Expectations in RCTs are not fixed and instead may be viewed as continuously shaped by multiple inputs that include experience and information received both before and during the trial. Variability in placebo response observed in previous studies may be related to the fluid nature of expectations. Trying to control and equalize expectations in RCTs may be more difficult than previously assumed.     

Surrogate endpoints in randomized cardiovascular clinical trials

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.     

Methodological issues in clinical trials of drug and behavior therapies

Trials that compare drug and behavior therapies or evaluate combination therapy raise special methodological issues. This article reviews these methodological issues and, where possible, offers guidelines for addressing them. Sources of bias in the selection and recruitment of participants and in the measurement of treatment outcomes are discussed. In addition, methodological problems presented by the differing structures of behavior and drug therapy, by confounding variables, such as allegiance effects, differential expectations and preferences for drug or behavior therapy, and differential adherence with drug or behavior therapy also are reviewed. Issues in the selection of appropriate control groups are also discussed.     

Balancing multiple baseline characteristics in randomized clinical trials

It is of vital importance to the success of a randomized clinical trial to maintain the balance of baseline characteristics (covariates) that could potentially confound the outcomes of the trial. Various randomization methods have been proposed to increase the likelihood of having balanced covariates at the end of a trial, most of which only apply to categorical covariates. An optimization approach to maintaining the balance of multiple covariates in randomized clinical trials is proposed, which is applicable to both continuous and categorical covariates and allows the covariates to be ranked according to their clinical importance as perceived by the clinical trial practitioners. Simulation results show that the proposed algorithm significantly outperforms the standard randomization approach via flipping an unbiased coin. The proposed randomization method can be easily implemented and generalized for cases where there are multiple treatment arms with equal or unequal randomization probabilities.     

Nurses' unique roles in randomized clinical trials.

Nurses are in an ideal position to promote patients' awareness of the role played by clinical trials in the advancement of health science and the subsequent improvement of patient care. The history of clinical trials and the four phases of clinical trials are described. Nurses' professional roles in clinical trial participation, such as helping the patient to identify open clinical trials and acting as clinical interpreter and patient advocate during the patient's participation in a trial, are detailed. Professional considerations that must be addressed by the nurse are reviewed and include ensuring that the trial has received approval from an Institutional Review Board for the participation of human subjects; that the responsibilities of participation are congruent with the nurse's personal values and workplace obligations; and that once engaged, the nurse can make the commitment to sustain participation in the trial. Most important, the nurse must keep the patient's needs and values uppermost in mind during the evaluation of potential clinical trials. Nurses have a critical role to play in the promotion of clinical trials, the recruitment of patients for clinical trial participation, the education of the patient and family, and the clinical care and support of patients throughout their participation in clinical trials.     

Detecting selection bias in randomized clinical trials.

Lack of concealment of allocation in randomized clinical trials can invite selection bias, which is the preferential enrollment of specific patients into one treatment group over another. For example, patients more likely to respond may be enrolled only when the next treatment to be assigned is known to be the active treatment, and patients less likely to respond may be enrolled only when the next treatment to be assigned is known to be the control. Despite the fact that selection bias can compromise both the internal and external validity of trials, little methodology has been developed for its detection. An investigator may test the success of the randomization by comparing baseline characteristics across treatment groups, but such test is limited by the potential inability of the measured baseline variables to predict response. A new method for detecting selections bias, based on response data only, is developed for the case in which a small block size, and either unmasking of treatment codes or an open-label design, have compromised the concealment of allocation. This new method complements baseline comparisons, and is sensitive to detect selection bias even in situations in which baseline comparisons are not.     

Estimating rates of change in randomized clinical trials

This article deals with the extension of the pretest-posttest clinical trial to the longitudinal data setting. We assume that a baseline (or pretest) measurement is taken on all individuals, who are then randomized, without regard to baseline values, to a treatment group. Repeated measurements are taken postrandomization at specified times. Our objective is to estimate the average rate of change (or slope) in the experimental groups and the differences in the slopes. Our focus is on the optimal use of the baseline measurements in the analysis. We contrast two different approaches:--a multivariate one that regards the entire vector of responses (including the baseline) as random outcomes and a univariate one that uses each individual's least squares slope as an outcome. Our multivariate approach is essentially a generalization of Stanek's Seemingly Unrelated Regression (SUR) estimator for the pretest-posttest design. The multivariate approach is natural to apply in this setting, and optimal if the assumed model is correct. However, the most efficient estimator requires assuming that the baseline mean parameters are the same for all experimental groups. Although this assumption is reasonable in the randomized setting, the resulting multivariate estimator uses postrandomization data as a covariate; if the assumed linear model is not correct, this can lead to distortions in the estimated treatment effect. We propose instead a reduced form multivariate estimator that may be somewhat less efficient, but protects against model misspecification.     

Blinding in randomized clinical trials: imposed impartiality

Blinding, or "masking," is a crucial method for reducing bias in randomized clinical trials. In this paper, we review important methodological aspects of blinding, emphasizing terminology, reporting, bias mechanisms, empirical evidence, and the risk of unblinding. Theoretical considerations and empirical analyses support the blinding of patients, health-care providers, and outcome assessors as to the trial intervention to which patients have been allocated. We encourage extensive pretrial testing of blinding procedures and explicit reporting of who was in the blinded condition and the methods used to ensure blinding.     

我国慢性胃炎治疗性研究的现状分析

目的：了解我国慢性胃炎治疗性研究的一般状况，特别是RCT／CCT的现状，以及能否为临床提供可靠的研究依据。方法：按中国循证医学中心及Cochrane手册标准对8种消化专业或与消化专业有关的临床中杂志逐篇人工查阅，登记所有慢性胃炎的临床治疗性研究，分析其中的RCT／CCT。结果：共查阅113卷823期，包括临床治疗性章214篇，并分析了RCT／CCT共81篇。结论：目前我国发表的慢性胃炎的防治性研究RCT／CCT的数量较少，质量差别大，还不能满足临床实践的需要，西药类药物防治性研究献RCT／CCT比例高于中医与中西医结合类药物。     

Power analysis in randomized clinical trials based on item response theory

Patient relevant outcomes, measured using questionnaires, are becoming increasingly popular endpoints in randomized clinical trials (RCTs). Recently, interest in the use of item response theory (IRT) to analyze the responses to such questionnaires has increased. In this paper, we used a simulation study to examine the small sample behavior of a test statistic designed to examine the difference in average latent trait level between two groups when the two-parameter logistic IRT model for binary data is used. The simulation study was extended to examine the relationship between the number of patients required in each arm of an RCT, the number of items used to assess them, and the power to detect minimal, moderate, and substantial treatment effects. The results show that the number of patients required in each arm of an RCT varies with the number of items used to assess the patients. However, as long as at least 20 items are used, the number of items barely affects the number of patients required in each arm of an RCT to detect effect sizes of 0.5 and 0.8 with a power of 80%. In addition, the number of items used has more effect on the number of patients required to detect an effect size of 0.2 with a power of 80%. For instance, if only five randomly selected items are used, it is necessary to include 950 patients in each arm, but if 50 items are used, only 450 are required in each arm. These results indicate that if an RCT is to be designed to detect small effects, it is inadvisable to use very short instruments analyzed using IRT. Finally, the SF-36, SF-12, and SF-8 instruments were considered in the same framework. Since these instruments consist of items scored in more than two categories, slightly different results were obtained.     

Sham interventions in randomized clinical trials of acupuncture--a review

BACKGROUND AND OBJECTIVES: For non-drug interventions such as acupuncture, it is difficult to establish placebo or sham controls that are both inert and indistinguishable. We reviewed sham-controlled clinical trials of acupuncture to investigate (a) which types of sham interventions have been used in the past; (b) in what respects true and sham interventions differed; and (c) whether trials using different types of sham yielded different results. METHODS: 47 randomized controlled trials comparing true and sham acupuncture interventions for pain and a variety of other conditions were identified from systematic reviews and through a search in PubMed. Details of patients, interventions, sham interventions and outcomes were extracted in a standardized manner. RESULTS: In two trials the sham intervention consisted of superficial needling of the true acupuncture points, four trials used true acupuncture points which were not indicated for the condition being treated, in 27 trials needles were inserted outside true acupuncture points, five trials used placebo needles and nine trials used pseudo-interventions such as switched off-laser acupuncture devices. True and sham interventions often differed in a variety of other variables, such as manipulation of needles, depth of insertion, achievement of an irradiating needling sensation (de-chi), etc. There was no clear association between the type of sham intervention used and the results of the trials. CONCLUSION: Randomized trials investigating the specific effects of acupuncture have used a great variety of sham interventions as controls. Summarizing all the different sham interventions as "placebo" controls seems misleading and scientifically unacceptable.     

Meta-analysis of dropout rates in randomized controlled clinical trials

Background

The interpretation of opioid studies in patients with chronic pain due to osteoarthritis is limited by a high dropout rate. Therefore, the implication of dropouts on the recommendation of opioids in chronic osteoarthritis pain was analyzed.

Data sources

The databases of Medline, Embase, the Cochrane Library, and the Internet from 1990?C2009 were searched.

Study selection

Two independent authors included randomized controlled clinical trials investigating the effects of chronic opioid treatment for the management of osteoarthritis pain. In order to calculate the odds ratio, only placebo-controlled trials were included.

Data extraction

The primary outcome parameter was the dropout rate. Secondarily, the effect size was calculated. Data extraction was conducted by two independent authors.

Results

A total of 19 studies reporting results of 3,871 treatment and 2,080 placebo outcomes were retrieved. Compared to placebo, opioid treatment was associated with a significantly increased total dropout rate (OR=1.3, 95%CI 1.2?C1.4). Discontinuation of treatment was related to adverse events (OR=4.0, 95%CI 3.4?C4.6). Lack of analgesia was associated with a significantly reduced dropout rate in opioid groups (OR=0.4, 95%CI 0.3?C0.5). Analgesic effects were significantly better in opioid-treated patients (p=0.01).

Conclusion

In spite of analgesic effects, many osteoarthritis patients prefer to stop chronic opioid use, because of adverse events. Therefore, opioids are not generally recommended in osteoarthritis.